The goal of this program is to further our understanding of the mechanisms that regulate the progression of cells from the G1 phase to the S phase of the cell cycle and to determine how specific oncoproteins (i.e. mutant CDK4, E1A and MDM2) and potential tumor suppressor proteins (p130 and p107) alter these critical regulatory pathways. In Project #1, Dr. Reddy, utilizing a transgenic mouse model system, plans to determine how a tumor-derived mutation in the cyclin-dependent kinase 4 (CDK4) alters G1 to S progression and mediates escape from cellular senescence in vitro and promotes tumorigenesis in vivo. In Project #2, Dr. Grana aims to define p130 phosphorylation events that occur as cells pass through late G1 and S phases of the cell cycle that appear to regulate p130 protein stability, the mechanisms that result in p130 depletion, and the biological significance of these events in senescence and transformation. Finally, in Project 3, Dr. Haines plans to characterize how the novel cell cycle control molecule MTBP regulates G1 to S progression and how the MDM2 oncoprotein negatively affects MTBP function. The program is also logistically supported by three Cores; a Transgenic Animal Core (A), a Virology/Cell Culture Core (B) and an Administrative Core (C). The cores will be essential for the successful completion of all research projects. The studies proposed under this Program Project should provide the scientific community with a better understanding of the mechanisms that regulate G1/S progression in mammalian cells and how activation of particular oncogenes alone or in combination with inactivation of tumor suppressor genes from this pathway leads to tumorigenesis.